Celebrex: Let the Trials Begin

Clinic Director Lora Clawson explains dosage information to Celebrex trial participant William Hupfeldt. Volunteers on the drug or on placebo are carefully monitored in the yearlong study.

It’s good for arthritis, it’s under study for Alzheimer’s, and last month, national trials got under way exploring the anti-inflammation drug Celebrex as a possible ALS therapy. At the Center for ALS Research and 24 other sites, volunteers in early stages of the disease have begun receiving daily high doses.

“Is it a cure? I don’t think so,” says Center neurologist Daniel Drachman, M.D., whose ideas prompted the trials. “But Celebrex may become part of a new, multi-therapy approach to ALS.”

Whether used for arthritis or ALS, the principle is the same: the drug inhibits a key enzyme, called COX-2, in the body’s inflammatory and other pathways.

Drachman knew that three destructive processes—inflammation, the release of molecules called free radicals and the excitotoxicity process—play a strong part in the downward spiral occurring in ALS patients’ motor neurons. Excitotoxicity refers to an excess of the nerve transmitter glutamate, which overstimulates neurons, causing harm. The inspiration for the study came when Drachman realized Celebrex could, in theory, damp down all three events.

The middleman here is a class of molecules called prostaglandins. These bio-active agents can turn up inflammation as well as lead to release of glutamate and production of free radicals. And the nervous-system enzyme that sparks prostaglandin assembly? It’s COX-2.

What piqued Drachman’s interest three years ago, he says, was a study that showed prostaglandins trigger release of glutamate by astrocytes—motor neurons’ neighboring cells. “And the effect spreads!” he says. “Glutamate stimulates neighboring astrocytes and motor neurons to release even more.” Drachman thought stemming the glutamate tide might help. He turned to Celebrex, a known COX-2 inhibitor, to block creation of the prostaglandin “trigger.”

Drachman teamed with Center Director Jeffrey Rothstein, M.D., Ph.D., to show—in mouse spinal cord cultures—that Celebrex could protect motor neurons from glutamate’s ravages. When they gave Celebrex-laced chow to mouse models of ALS, they saw “a notable delay in symptom onset,” says Rothstein, “and the mice lived 25 percent longer as well.

“What’s more,” he says, “we’ve shown that, at this dosage, Celebrex does what it’s supposed to do: inhibit COX-2 in animals’ spinal cords and brains. That’s good news for an oral drug you’re eyeing for patients.”

Now Rothstein’s aiming one step upstream: inhibiting COX-2 may be useful, but how about blocking its production altogether? With a biotech firm, he’s helping develop something to waylay the signal to produce COX-2.

Next > Sponging Up Glutamate? Good Idea
A new study by Center scientist Margaret Sutherland, Ph.D., not only shores up a long-held idea on a major source of cell damage in ALS but also shows something can be done to fix it, at least in mice.